Angiogenesis, after birth, occurs by interactions between preexisting endothelial cells and angiogenic stem cells. Angiogenic stem cells include endothelial progenitor cells (EPCs) and endothelial colony forming cells (ECFCs). In the angiogenesis process, preexisting endothelial cells generate new blood vessels through proliferation, migration, infiltration, and vascular tube formation. However, due to various factors, such as chronic exposure to high levels of glucose and cholesterol, smoking, stress, lack of exercise, environmental factors, aging, etc., the activity of preexisting endothelial cells deteriorates, which leads to incomplete angiogenesis and ischemic cardiovascular diseases. Angiogenic stem cells, which are core cells involved in angiogenesis with preexisting endothelial cells, are mainly derived from bone marrow, transported into a site where angiogenesis is required, and differentiated into vascular endothelial cells, to participate in angiogenesis. According to numerous studies, angiogenic stem cells have been found to be critical to angiogenesis after birth. Thus, many studies are ongoing to mobilize angiogenic stem cells from bone marrow to peripheral blood. It was known that various cytokines including granulocyte colony-stimulating factor (GCSF), granulocyte/macrophage colony stimulating factor (GM-CSF), stromal cell-derived factor-1 (SDF-1), or vascular endothelial growth factor (VEGF), are effective in mobilizing angiogenic stem cells from bone marrow. However, these cytokines mobilize not only angiogenic stem cells but also inflammation causing cells. Thus, actual application of these cytokines poses various challenges.
Recently, a cell therapy product using stem cells draw attention as a novel therapy method for repairing damaged tissue or treating refractory diseases. Stem cells have pluripotency and explosive self-replicating capability, and thus have potential of overcoming limits of surgery operations, medicinal therapy, or gene therapy. However, in order for stem cells to be used as a cell therapy product, the following prerequisites should be satisfied. First, a sufficient amount of healthy stem cells should be obtained from patients. Second, when stem cells are transplanted, high transplantation rate should be secured in damaged tissue or a site for treatment. Third, when a stem cell therapy product is transplanted, it should be accurately differentiated into desired cells, organs, or tissue. In order to meet these prerequisites, numerous studies continue to develop in vitro expansion for obtaining a sufficient number of stem cells, various transplantation methods for increasing transplantation efficiency, differentiation induction, etc. Despite these efforts, there are still issues to be resolved in relation with acquisition of stem cells with degraded functions due to various disease risk factors patients have when the stem cells are extracted from the patients, senescence of stem cells occurring upon in vitro expansion, etc.
Meanwhile, tauroursodeoxycholic acid (TUDCA), bill acid, is the taurine conjugate form of ursodeoxycholic acid (UDCA). TUDCA acts as a chemical chaperone to maintain protein stability. According to various reports, it was disclosed that TUDCA has excellent effects as a therapeutic agent for cholestatic liver disease including primary biliary cirrhosis or primary sclerosing cholangitis. Also, TUDCA has been found to have neuroprotective effects by suppressing inflammatory response in ischemic brain diseases. Studies in recent years are proving the effects of TUDCA through mechanisms of preventing apoptosis, such as protection of liver cells, inhibition of neointimal hyperplasia, maintenance of constant sugar, etc. Further, various studies are conducted to treat various refractory diseases including Huntington's disease, Parkinson's disease, and stroke. TUDCA for cells has great effects in preventing apoptosis. Particularly, TUDCA controls the apoptosis signal transmission system which is proceeded in the mitochondria, and prevents apoptosis with its role by promoting the activation of anti-apoptotic signal factors. Moreover, TUDCA suppresses endoplasmic reticulum stress (ER-stress), thereby protecting cells in damaged tissue.
In spite of continual studies on the effect of TUDCA, a cell therapy product using TUDCA has not been developed. Particularly, it was not found out whether TUDCA has excellent angiogenesis and revascularization effects, repairs senescent stem cells, and promotes bioactivity of angiogenic stem cells. Further, no attempts were made to apply TUDCA for overcoming the obstacles to conventional stem cell therapy, which are limited supply of stem cells, senescence of transplanted stem cells and lower survival rate thereof in ischemic tissue, degradation of differentiation into blood vessels, etc.